No Clear Value for Aspirin in Primary Cardioprevention

Action Points

Explain to interested patients that primary prevention attempts to avoid cardiovascular events in people who do not have heart disease, whereas secondary prevention is begun after someone has a coronary event.

Note that U.S. Preventive Services Task Force and American Heart Association guidelines recommend aspirin for primary prevention in patients at moderately elevated risk for heart disease.

SAN FRANCISCO, May 28 -- Long-term, low-dose aspirin provides no clear net value for primary prevention of cardiovascular events in apparently healthy adults, according to a meta-analysis of patient-level data.

In people not known to have cardiovascular disease, aspirin reduced composite MI, stroke, and vascular death rates to 0.51% per year compared with 0.57% among controls (P=0.0001) for a relative 12% reduction, according to Colin Baigent, B.M.B.Ch., of the University of Oxford, England, and colleagues in the Antithrombotic Trialists' Collaboration.

But the major gastrointestinal and extracranial bleeding rate rose from 0.07% per year among controls to 0.10% among those receiving aspirin for primary prevention (P<0.0001), the researchers reported in the May 30 issue of The Lancet.

Importantly, the bleeding risk rose right along with cardiovascular risk level, the cooperative group said.

Guidelines from the U.S. Preventive Services Task Force and the American Heart Association largely ignore any differences in bleeding risk, and recommend wide use of aspirin for primary prevention in patients at moderately elevated heart disease risk, the researchers noted.

However, there was no threshold cardiovascular risk level that appeared to have a sufficient benefit-to-bleeding risk ratio among the 95,000 participants in the six long-term primary prevention trials included in the meta-analysis, Dr. Baigent said.

"Current guidelines may need to be reviewed," he said.

For primary prevention, "the main strategies ought to be really stopping smoking -- if people smoke -- then if further measures are needed, lowering blood pressure, lowering cholesterol," Dr. Baigent said. "The benefits of adding aspirin to all that does not clearly outweigh the hazards."

In the meta-analysis, the benefit for major coronary event risk reduction was driven by a 23% proportional reduction in nonfatal MI (0.18% with aspirin versus 0.23% for controls per year, P<0.0001).

The number needed to treat for one year to prevent one nonfatal heart attack was 2,000, Dr. Baigent said.

The relative risk reduction appeared similar for men and women (P=0.9) and for those at each level of cardiovascular risk (P=0.3 for trend with predicted 5-year risk of coronary heart disease rising from less than 2.5% to 10% or more).

Older age, male sex, diabetes, and high blood pressure were associated with significantly elevated absolute ischemic stroke and major coronary event risk, but also with significantly increased risk of major extracranial bleeding and at least a trend for hemorrhagic stroke as well.

Primary prevention with aspirin could be expected to prevent five nonfatal heart attacks but cause three extra gastrointestinal bleeds and one extra intracranial hemorrhage per 10,000 people treated per year, Dr. Baigent said.

"Hence, although the currently available trial results could well help inform personally appropriate judgments by individuals about their own use of long-term aspirin," the researchers concluded, "they do not seem to justify general guidelines advocating the routine use of aspirin in all apparently healthy individuals above a moderate level of risk of coronary heart disease."

However, an accompanying commentary came to a different conclusion -- that gender and baseline risk matter.

Ale Algra, M.D., and Jacoba P. Greving, Ph.D., both of the University Medical Centre Utrecht in the Netherlands, used the meta-analysis data to calculate cost effectiveness for men and women separately.

Based on incremental cost effectiveness, they recommended aspirin for the following:

Men age 50 to 59 who are at five times the average cardiovascular risk

Men age 60 to 69, who have at least twice the average cardiovascular risk and women in the same age range with at least five times the average cardiovascular risk

All men age 70 to 79 regardless of risk and women in the same age range with at least double the average cardiovascular risk

Both the researchers and the commentators noted that adding statins to the mix in primary prevention complicates the picture.

The researchers noted that the aspirin primary prevention trials in their meta-analysis included few participants who were taking statins.

Since statins reduce both MI and ischemic stroke risk with little bleeding hazard and low cost for generics, "primary prevention by a statin could well be preferred to primary prevention only by aspirin," they wrote.

Adding aspirin to a statin would likely cut aspirin's expected benefit in half while doing nothing to reduce the bleeding risk, they added.

The meta-analysis also included 16 secondary prevention trials among 17,000 people at high risk with results consistent with all prior research suggesting a benefit for nonfatal cardiovascular disease as well as overall mortality that outweighed bleeding risk.

The Clinical Trial Service Unit and Epidemiological Studies Unit, where the collaboration's secretariat is located, reported involvement in clinical trials of cholesterol modification therapy and of antiplatelet therapy with funding from the Medical Research Council, British Heart Foundation, and companies including Bayer, Merck, Merck Schering Plough, Solvay and the Aspirin Foundation.

Several of Dr. Baigent's co-authors reported conflicts of interest with Bayer. Dr. Algra reported conflicts of interest with Boehringer Ingelheim.

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